1. Arnold Anteraper S, Guell X, Taylor HPI, D’Mello A, Whitfield-Gabrieli S, Joshi G. {{Intrinsic Functional Connectivity of Dentate Nuclei in Autism Spectrum Disorder}}. {Brain Connect};2019 (Oct 8)
Cerebellar abnormalities are commonly reported in autism spectrum disorder (ASD). Dentate nuclei (DN) is a key structure in the anatomical circuits linking the cerebellum to the extracerebellum. Previous resting-state functional connectivity (RsFc) analyses reported DN abnormalities in high-functioning ASD (HF-ASD). This study examined the RsFc of the DN in young adults with HF-ASD compared to healthy controls (HC) with the aim to expand upon previous findings of DN in a dataset using advanced imaging acquisition methods that optimize spatiotemporal resolution and statistical power. Additional seed-to-voxel analyses were carried out using motor and non-motor DN coordinates reported in previous studies as seeds. We report abnormal dentato-cerebral and dentato-cerebellar functional connectivity in ASD. Our results expand and in part replicate previous descriptions of DN RsFc abnormalities in this disorder, and reveal correlations between DN-cerebral RsFc and ASD symptom severity.
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2. Berry-Kravis E, Kidd SA, Lachiewicz AM, Choo TH, Tartaglia N, Talapatra D, Aguirre-Kolb C, Andrews H, Riley K. {{Toilet Training in Fragile X Syndrome}}. {J Dev Behav Pediatr};2019 (Oct 4)
OBJECTIVE: To characterize bladder and bowel toileting skill acquisition in children with fragile X syndrome and to identify associated demographic, behavioral, and clinical factors. METHODS: Using baseline data from the Fragile X Online Registry With Accessible Research Database (FORWARD), bivariate analyses and logistic regression models were used to identify differences between subjects who were and were not bowel and/or bladder trained by the age of 10 years. Cox proportional hazard models were used to assess the rate of completion of toilet training (TT) as a function of sex and autism spectrum disorder (ASD) diagnosis. RESULTS: In bivariate analyses, male sex, lower language level, inability to write one’s name, more impaired intellectual level, ASD, and more severe behavioral deficits all predicted lack of bladder training (n = 313, p < 0.001) and bowel training (n = 300, p = 0.0004-0.0001) by the age of 10 years. In logistic regression models, lower level of language acquisition (p < 0.001) and higher Aberrant Behavior Checklist Irritability scores (p < 0.04) were associated with lower odds of bladder training by the age of 10 years. Lower level of language acquisition (p < 0.001) and ASD (p < 0.025) were associated with lower odds of bowel training by the age of 10 years. For both bladder and bowel training, Cox proportional hazard models indicated that delayed training was associated with male sex, lower levels of language acquisition, and ASD for both bladder training (n = 486; p < 0.001) and bowel training (n = 472; p < 0.001). CONCLUSION: These findings emphasize the importance of both slower language development and ASD diagnosis in predicting bowel and bladder training delays and can be used to develop and evaluate targeted approaches to TT based on sex, ASD diagnosis, and other clinical features identified in this study. Lien vers le texte intégral (Open Access ou abonnement)
3. Busch RM, Srivastava S, Hogue O, Frazier TW, Klaas P, Hardan A, Martinez-Agosto JA, Sahin M, Eng C. {{Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN}}. {Transl Psychiatry};2019 (Oct 8);9(1):253.
Germline mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and are associated with marked abnormalities in the white matter of the brain. This study sought to characterize the neurobehavioral phenotype of PTEN-ASD. Comprehensive neurobehavioral evaluations were conducted in 36 participants (ages 3-21 years) with PTEN-ASD and compared to two groups of controls: non-syndromic ASD with macrocephaly (Macro-ASD, n = 25) and those with PTEN mutations without ASD (PTEN-no ASD, n = 23). Linear regression analysis or Kruskal-Wallis tests were used to examine group differences on neurobehavioral measures (cognitive, behavioral, sensory, and adaptive functioning) and, for select measures, one-sample t-tests were used to compare group performance to healthy control norms. These analyses revealed a distinct neuropsychological profile associated with mutations in PTEN suggesting primary disruption of frontal lobe systems (i.e., attention, impulsivity, reaction time, processing speed, and motor coordination). Cognitive deficits in PTEN-ASD are more severe than those in PTEN-no ASD and extend to other areas of neurobehavioral function, specifically, adaptive behavior and sensory deficits. While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities suggestive of less sensory responsiveness. Together, these results suggest that PTEN-ASD has a distinct neurobehavioral phenotype compared to idiopathic ASD that is likely to warrant special consideration for overall assessment and treatment.
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4. Chang YS, Lin CY, Huang HY, Chang JG, Kuo HT. {{Chromosomal microarray and whole-exome sequence analysis in Taiwanese patients with autism spectrum disorder}}. {Mol Genet Genomic Med};2019 (Oct 8):e996.
BACKGROUND: Autism spectrum disorder (ASD) is defined as a group of genetically and clinically heterogeneous neurodevelopmental disorders. Interplay between de novo and inherited rare variants has been suspected in the development of ASD. METHODS: Here, we applied 750K oligonucleotide microarray analysis and whole-exome sequencing (WES) to five trios from Taiwanese families with ASD. RESULTS: The chromosomal microarray analysis revealed three representative known diagnostic copy number variants that contributed to the clinical presentation: the chromosome locations 2q13, 1q21.1q21.2, and 9q33.1. WES detected 22 rare variants in all trios, including four that were newly discovered, one of which is a de novo variant. Sequencing variants of JMJD1C, TCF12, BIRC6, and NHS have not been previously reported. A novel de novo variant was identified in NHS (p.I7T). Additionally, seven pathogenic variants, including SMPD1, FUT2, BCHE, MYBPC3, DUOX2, EYS, and FLG, were detected in four probands. One of the involved genes, SMPD1, had previously been reported to be mutated in patients with Parkinson’s disease. CONCLUSIONS: These findings suggest that de novo or inherited rare variants and copy number variants may be double or multiple hits of the probands that lead to ASD. WES could be useful in identifying possible causative ASD variants.
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5. Cruz-Torres E, Duffy ML, Brady MP, Bennett KD, Goldstein P. {{Promoting Daily Living Skills for Adolescents with Autism Spectrum Disorder via Parent Delivery of Video Prompting}}. {J Autism Dev Disord};2019 (Oct 8)
The use of technological devices has proven to be effective and efficient for the delivery of videos aimed at promoting daily living skills (DLS) among individuals with autism spectrum disorder. As technology advances, devices have become more portable and, ultimately, accessible to caregivers. There are relatively few studies that have examined whether parents can be taught to effectively deliver evidence-based practices using portable, mainstream devices. Using a multiple baseline across participants design, we evaluated parent fidelity in the delivery of video prompts on an iPad to their children who were learning DLS. Results indicated that parents were successful in their delivery of the training procedures and their children acquired and maintained the skills.
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6. DesChamps TD, Ibanez LV, Edmunds SR, Dick CC, Stone WL. {{Parenting stress in caregivers of young children with ASD concerns prior to a formal diagnosis}}. {Autism Res};2019 (Oct 8)
Robust findings demonstrate that parents of children with autism spectrum disorder (ASD) experience high levels of parenting stress that are associated with negative outcomes for families. Although the majority of research on parenting stress has focused on parents of children with an existing diagnosis, parents of young children with concerns about ASD-related behaviors also face many unique challenges before the time of diagnosis. However, no study to date has examined patterns of parenting stress among parents of children with ASD concerns prior to a formal ASD diagnosis. Therefore, the current study investigated longitudinal trajectories of parenting stress among parents of young children with ASD concerns compared to parents of children with non-ASD developmental concerns (e.g., language delay), and parents of children with no developmental concerns. Known predictors of parenting stress were also examined. Results from multilevel model analyses revealed that parents of children with ASD concerns experienced consistently higher levels of parenting stress across early child development compared to parents of children with non-ASD developmental concerns and those with no concerns. Additionally, parenting efficacy, psychological functioning, social satisfaction, and child social communication behaviors predicted levels of parenting stress for all parents. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study examined parenting stress across time among parents of young children with ASD concerns before receiving a diagnosis. Parents of children with ASD concerns reported consistently higher levels of parenting stress compared to parents of children with other developmental concerns and parents of children with no concerns. Also, ASD concerns predicted parenting stress in addition to other parent and child predictors of parenting stress. These findings highlight the need to better support families before an ASD diagnosis.
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7. Di Pierro D, Ciaccio C, Sbardella D, Tundo GR, Bernardini R, Curatolo P, Galasso C, Pironi V, Coletta M, Marini S. {{Effects of oral administration of common antioxidant supplements on the energy metabolism of red blood cells. Attenuation of oxidative stress-induced changes in Rett syndrome erythrocytes by CoQ10}}. {Mol Cell Biochem};2019 (Oct 8)
Nutritional supplements are traditionally employed for overall health and for managing some health conditions, although controversies are found concerning the role of antioxidants-mediated benefits in vivo. Consistently with its critical role in systemic redox buffering, red blood cell (RBC) is recognized as a biologically relevant target to investigate the effects of oxidative stress. In RBC, reduction of the ATP levels and adenylate energy charge brings to disturbance in intracellular redox status. In the present work, several popular antioxidant supplements were orally administrated to healthy adults and examined for their ability to induce changes on the energy metabolism and oxidative status in RBC. Fifteen volunteers (3 per group) were treated for 30 days per os with epigallocatechin gallate (EGCG) (1 g green tea extract containing 50% EGCG), resveratrol (325 mg), coenzyme Q10 (CoQ10) (300 mg), vitamin C (1 g), and vitamin E (400 U.I.). Changes in the cellular levels of high-energy compounds (i.e., ATP and its catabolites, NAD and GTP), GSH, GSSG, and malondialdehyde (MDA) were simultaneously analyzed by ion-pairing HPLC. Response to oxidative stress was further investigated through the oxygen radical absorptive capacity (ORAC) assay. According to our experimental approach, (i) CoQ10 appeared to be the most effective antioxidant inducing a high increase in ATP/ADP, ATP/AMP, GSH/GSSG ratio and ORAC value and, in turn, a reduction of NAD concentration, (ii) EGCG modestly modulated the intracellular energy charge potential, while (iii) Vitamin E, vitamin C, and resveratrol exhibited very weak effects. Given that, the antioxidant potential of CoQ10 was additionally assessed in a pilot study which considered individuals suffering from Rett syndrome (RTT), a severe X-linked neuro-developmental disorder in which RBC oxidative damages provide biological markers for redox imbalance and chronic hypoxemia. RTT patients (n = 11), with the typical clinical form, were supplemented for 12 months with CoQ10 (300 mg, once daily). Level of lipid peroxidation (MDA production) and energy state of RBCs were analyzed at 2 and 12 months. Our data suggest that CoQ10 may significantly attenuate the oxidative stress-induced damage in RTT erythrocytes.
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8. DiStasio MM, Nagakura I, Nadler MJ, Anderson MP. {{T-lymphocytes and Cytotoxic Astrocyte Blebs Correlate Across Autism Brains}}. {Ann Neurol};2019 (Oct 8)
OBJECTIVE: Autism spectrum disorder (ASD) affects 1 in 59 children yet, except for rare genetic causes, the etiology in most ASD remains unknown. In the ASD brain, inflammatory cytokine and transcript profiling show increased expression of genes encoding mediators of the innate immune response. We evaluated post-mortem brain tissue for adaptive immune cells and immune cell-mediated cytotoxic damage that could drive this innate immune response in the ASD brain. METHODS: Standard neuropathology diagnostic methods including histology and immunohistochemistry were extended with automated image segmentation to quantify identified pathologic features in the postmortem brains. RESULTS: We report multifocal perivascular lymphocytic cuffs contain increased numbers of lymphocytes in ~65% of ASD compared to control brains in males and females, across all ages, in most brain regions, and in white and grey matter, and leptomeninges. CD3(+) T-lymphocytes predominate over CD20(+) B-lymphocytes and CD8(+) over CD4(+) T-lymphocytes in ASD brains. Importantly, the perivascular cuff lymphocytes numbers correlate to the quantity of astrocyte-derived round membranous blebs. Membranous blebs form as a cytotoxic reaction to lymphocyte attack. Consistent with multifocal immune cell-mediated injury at perivascular CSF-brain barriers, a subset of white matter vessels have increased perivascular space (with jagged contours) and collagen in ASD compared to control brains. CSF-brain barrier pathology is also evident at cerebral cortex pial and ventricular ependymal surfaces in ASD. INTERPRETATION: The findings suggest dysregulated cellular immunity damages astrocytes at foci along the CSF-brain barrier in ASD. This article is protected by copyright. All rights reserved.
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9. Espinoza KM, Doomes AS. {{Peer teaching of clinically complex developmental disability cases}}. {Med Educ};2019 (Oct 7)
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10. Green J. {{Editorial Perspective: Delivering autism intervention through development}}. {J Child Psychol Psychiatry};2019 (Oct 9)
Autism is a priority condition within global health and represents a significant public health challenge. In this Editorial, I argue for a new perspective on how this challenge might be met, based on the idea of autism as an enduring developmental condition and focused on the family as a key resource. Drawing on models from management of enduring conditions elsewhere in health and on recent autism intervention science, I make the case for a developmental sequence of pulsed interventions, initially focused on early family resilience and self-management, along with case management and timely step-up care to specialist management.
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11. Kahathuduwa CN, West BD, Blume J, Dharavath N, Moustaid-Moussa N, Mastergeorge A. {{The risk of overweight and obesity in children with autism spectrum disorders: A systematic review and meta-analysis}}. {Obes Rev};2019 (Oct 8)
Multiple studies have suggested that autism spectrum disorders seem to increase the risk of overweight and obesity. We examined the pooled prevalence and relative risk of developing overweight or obesity among children with autism spectrum disorders in a systematic review and meta-analysis. We searched PubMed, Scopus, ProQuest, and Web of Science databases and subsequently screened the records to identify studies that reported prevalence of overweight and/or obesity in children with ASD and matched groups of neurotypical children. DerSimonian-Laird random-effects meta-analyses were performed to examine pooled prevalence and relative risk of obesity in children with autism spectrum disorders using the « meta » package in R software. Among children with autism spectrum disorders, the prevalence of obesity was 22.2%. Children with ASD had a 41.1% greater risk (P = .018) of development of obesity. Non-Caucasian race, increasing age, female sex, and living in the United States emerged as positive moderators of the association between autism spectrum disorders and prevalence of overweight or obesity. Autism spectrum disorders seem to increase the risk of childhood obesity. Increased awareness of this association may allow the implementation of early interventions to reduce obesity and prevent potential deterioration of quality-of-life in this population.
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12. Khanbabaei M, Hughes E, Ellegood J, Qiu LR, Yip R, Dobry J, Murari K, Lerch JP, Rho JM, Cheng N. {{Precocious myelination in a mouse model of autism}}. {Transl Psychiatry};2019 (Oct 7);9(1):251.
Autism spectrum disorder (ASD) has been hypothesized to be a result of altered connectivity in the brain. Recent imaging studies suggest accelerated maturation of the white matter in young children with ASD, with underlying mechanisms unknown. Myelin is an integral part of the white matter and critical for connectivity; however, its role in ASD remains largely unclear. Here, we investigated myelin development in a model of idiopathic ASD, the BTBR mice. Magnetic resonance imaging revealed that fiber tracts in the frontal brain of the BTBR mice had increased volume at postnatal day 6, but the difference reduced over time, reminiscent of the findings in young patients. We further identified that myelination in the frontal brain of both male and female neonatal BTBR mice was increased, associated with elevated levels of myelin basic protein. However, myelin pattern was unaltered in adult BTBR mice, revealing accelerated developmental trajectory of myelination. Consistently, we found that signaling of platelet-derived growth factor receptor alpha (PDGFRalpha) was reduced in the frontal brain of neonatal BTBR mice. However, levels of microRNA species known to regulate PDGFRalpha signaling and myelination were unaltered. Together, these results suggest that precocious myelination could potentially contribute to increased volume and connectivity of the white matter observed in young children with ASD.
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13. McDaniel J, Yoder P, Estes A, Rogers SJ. {{Validity of Vocal Communication and Vocal Complexity in Young Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2019 (Oct 9)
To identify valid measures of vocal development in young children with autism spectrum disorder in the early stages of language learning, we evaluated the convergent validity, divergent validity, and sensitivity to change (across 12 months) of two measures of vocal communication and two measures of vocal complexity through conventional coding of communication samples. Participants included 87 children with autism spectrum disorder (M = 23.42 months at entry). All four vocal variables demonstrated consistent evidence of convergent validity, divergent validity, and sensitivity to change with large effect sizes for convergent validity and sensitivity to change. The results highlight the value of measuring vocal communication and vocal complexity in future studies.
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14. McGuinn LA, Windham GC, Kalkbrenner AE, Bradley C, Di Q, Croen LA, Fallin MD, Hoffman K, Ladd-Acosta C, Schwartz J, Rappold AG, Richardson DB, Neas LM, Gammon MD, Schieve LA, Daniels JL. {{Early Life Exposure to Air Pollution and Autism Spectrum Disorder: Findings from a Multisite Case-Control Study}}. {Epidemiology};2019 (Oct 1)
BACKGROUND: Epidemiologic studies have reported associations between prenatal and early postnatal air pollution exposure and autism spectrum disorder (ASD); however, findings differ by pollutant and developmental window. OBJECTIVES: We examined associations between early life exposure to PM2.5 and ozone in association with ASD across multiple US regions. METHODS: Our study participants included 674 children with confirmed ASD and 855 population controls from the Study to Explore Early Development, a multi-site case-control study of children born from 2003 to 2006 in the United States. We used a satellite-based model to assign air pollutant exposure averages during several critical periods of neurodevelopment: 3 months before pregnancy; each trimester of pregnancy; the entire pregnancy; and the first year of life. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs), adjusting for study site, maternal age, maternal education, maternal race/ethnicity, maternal smoking, and month and year of birth. RESULTS: The air pollution-ASD associations appeared to vary by exposure time period. Ozone exposure during the third trimester was associated with ASD, with an OR of 1.2 (95% CI: 1.1, 1.4) per 6.6 ppb increase in ozone. We additionally observed a positive association with PM2.5 exposure during the first year of life [OR = 1.3 (95% CI: 1.0, 1.6) per 1.6 microg/m increase in PM2.5]. CONCLUSIONS: Our study corroborates previous findings of a positive association between early life air pollution exposure and ASD, and identifies a potential critical window of exposure during the late prenatal and early postnatal periods.
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15. Mohammadi S, Asadi-Shekaari M, Basiri M, Parvan M, Shabani M, Nozari M. {{Improvement of autistic-like behaviors in adult rats prenatally exposed to valproic acid through early suppression of NMDA receptor function}}. {Psychopharmacology (Berl)};2019 (Oct 8)
RATIONALE: Autism spectrum disorder (ASD), the fastest growing neurodevelopmental disorder, is characterized by social deficits, repetitive/stereotypic activity, and impaired verbal and nonverbal communication and is commonly diagnosed at early stages of life. Based on the excitatory-inhibitory imbalance theory of autism, some recent animal experiments have reported amelioration in autistic-like phenotypes in adult animals following acute treatment of NMDA antagonists. However, we suggested the neonatal period as a critical period for NMDA antagonist intervention. OBJECTIVES: This experiment was designed to determine the role of postnatal MK-801, an NMDA receptor blocker, in the prenatal valproic acid (VPA) rat model of ASD. METHODS: The model of autism was induced by subcutaneous administration of valproic acid (600 mg/kg) to pregnant rats at gestational day 12.5. The effects of MK-801 (0.03 mg/kg, from postnatal day 6-10) in correcting ASD-associated behaviors in male offspring were assessed by open-field, three-chambered social interaction tests. Moreover, the nociceptive threshold was measured by tail flick and hot plate. Behavioral tests were performed on PND 55-60. Nissl staining was performed to confirm the safety of 0.03 mg/kg MK-801 for the brain. RESULTS: We reported that MK-801 rescued social deficits, repetitive behaviors (self-grooming), anxiety-related behavior, and the low nociceptive threshold in the VPA-treated rats. Further, histological examination showed that there were no significant differences among all the groups in terms of the neuronal survival rate. CONCLUSIONS: Our results showed that postnatal low-dose MK-801 improved ASD-associated behaviors in the VPA-treated rats and that early exposure to NMDA antagonist resulted in permanent changes in adult behavior.
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16. Park SH, Demetriou EA, Pepper KL, Song YJC, Thomas EE, Hickie IB, Glozier N, Guastella AJ. {{Replication of the psychometric properties of the WHODAS-II in individuals with autism spectrum disorder}}. {Autism Res};2019 (Oct 8)
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17. Skogstrand K, Hagen CM, Borbye-Lorenzen N, Christiansen M, Bybjerg-Grauholm J, Baekvad-Hansen M, Werge T, Borglum A, Mors O, Nordentoft M, Mortensen PB, Hougaard DM. {{Reduced neonatal brain-derived neurotrophic factor is associated with autism spectrum disorders}}. {Transl Psychiatry};2019 (Oct 7);9(1):252.
Mental disorders have for the majority of cases an unknown etiology, but several studies indicate that neurodevelopmental changes happen in utero or early after birth. We performed a nested case-control study of the relation between blood levels of neuro-developmental (S100B, BDNF, and VEGF-A) and inflammatory (MCP-1, TARC, IL-8, IL-18, CRP, and IgA) biomarkers in newborns, and later development of autism spectrum disorders (ASD, N = 751), attention deficit hyperactivity disorders (ADHD, N = 801), schizophrenia (N = 1969), affective (N = 641) or bipolar disorders (N = 641). Samples and controls were obtained as part of the iPSYCH Danish Case-Cohort Study using dried blood spot samples collected between 1981 and 2004, and stored frozen at the Danish National Biobank. In newborns lower blood level of BDNF was significantly associated with increased odds (OR 1.15) of developing ASD (p = 0.001). This difference could not be explained by genetic variation in the BDNF coding gene region. A tendency of decreased levels of all the neurotrophic markers and increased levels of all inflammatory markers was noted. The low newborn blood levels of BDNF in children developing ASD is an important finding, suggesting that lower BDNF levels in newborns contributes to the etiology of ASD and indicates new directions for further research. It may also help identifying a long-sought marker for high-ASD risk in, e.g., younger siblings of ASD children.
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18. Suren P, Havdahl A, Oyen AS, Schjolberg S, Reichborn-Kjennerud T, Magnus P, Bakken IJL, Stoltenberg C. {{Diagnosing autism spectrum disorder among children in Norway}}. {Tidsskr Nor Laegeforen};2019 (Oct 8);139(14)
BACKGROUND: The percentage share of children who are diagnosed with autism spectrum disorder has increased considerably since the 1990s in Norway as well as in other countries. It has previously been demonstrated that there is considerable variation between counties with respect to diagnostic practice. MATERIAL AND METHOD: We calculated the percentage of children with autism spectrum disorder by using patient data obtained from the Norwegian Patient Registry and population data obtained from the National Registry. The calculations were made for the country as a whole as well as by county. The diagnostic assessments and documentation were mapped by linking the Norwegian Patient Registry with the Norwegian Mother, Father and Child Cohort study. We also reviewed patient records obtained from the specialist health service and considered whether diagnostic practice satisfied the research criteria for autism spectrum disorder. RESULTS: By the age of eight, 1.1 % of boys and 0.3 % of girls had been diagnosed with autism spectrum disorder. The overall percentages varied from 0.3 to 1.0 between counties. From 2008 to 2016, these percentages increased in all age groups. Our review of patient records included 503 children. In 95 % of cases the patient records provided a high standard of documentation that the diagnostic research criteria had been satisfied. The assessments were largely conducted in accordance with the guidelines drawn up by the various health trusts. INTERPRETATION: Autism diagnoses are generally well documented within the Norwegian specialist health service and meet the diagnostic criteria. In the counties that demonstrate a low prevalence of autism, it appears the health service fails to recognise autism in many children, particularly girls, or the diagnosis is determined late.
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19. Tamouza R, Fernell E, Eriksson MA, Anderlid BM, Manier C, Mariaselvam CM, Boukouaci W, Leboyer M, Gillberg C. {{HLA Polymorphism in Regressive and Non-Regressive Autism: A Preliminary Study}}. {Autism Res};2019 (Oct 8)
Autism spectrum disorders (ASD) comprises heterogeneous neurodevelopmental conditions with symptom onset usually during infancy. However, about 10%-30% of affected cases experience a loss of language and social skills around 18-30 months, so-called regressive autism. In this subset with regression, immune dysfunctions including inflammation and autoimmunity have been proposed to be at risk factors. Given the implication of the human histocompatibility antigens (HLA) system in various aspects of immune responses, including autoimmunity, and in ASD, we investigate here the distribution of the HLA Class I and Class II haplotypes in 131 children with ASD meeting DSM-IV TR criteria, with and without regression. We found that 62 of the 98 non-regressive ASD patients carry the HLA-DPA1*01-DPB1*04 sub-haplotype as compared to 14 of the 33 patients with regression (63% vs. 43% respectively, Pc = 0.02), suggesting that this HLA haplotype may exert a protective effect against regression. Similarly, the HLA-DPA1*01-DPB1*04 has also been found to be more represented in healthy controls as compared to patients affected with common nonpsychiatric autoimmune disorders. Overall our findings suggest a possible involvement of HLA polymorphism in the context of regressive ASD. (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Immune dysfunctions including inflammatory and autoimmune processes have been reported in autism, particularly in regressive forms. In this study, we analyzed the distribution of HLA haplotypes among children with autism spectrum disorder (ASD), with and without regression from Sweden and observed that HLA-DPA1*01-DPB1*04 sub-haplotype was less represented in patients with regressive autism as compared with those without regression. Such possible protective effect, also observed in other common autoimmune disorders, may constitute a link between HLA-mediated immune processes and regressive ASD.
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20. Tsilioni I, Patel AB, Pantazopoulos H, Berretta S, Conti P, Leeman SE, Theoharides TC. {{IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin}}. {Proc Natl Acad Sci U S A};2019 (Oct 7)
Autism spectrum disorder (ASD) does not have a distinct pathogenesis or effective treatment. Increasing evidence supports the presence of immune dysfunction and inflammation in the brains of children with ASD. In this report, we present data that gene expression of the antiinflammatory cytokine IL-37, as well as of the proinflammatory cytokines IL-18 and TNF, is increased in the amygdala and dorsolateral prefrontal cortex of children with ASD as compared to non-ASD controls. Gene expression of IL-18R, which is a receptor for both IL-18 and IL-37, is also increased in the same brain areas of children with ASD. Interestingly, gene expression of the NTR3/sortilin receptor is reduced in the amygdala and dorsolateral prefrontal cortex. Pretreatment of cultured human microglia from normal adult brains with human recombinant IL-37 (1 to 100 ng/mL) inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1beta and CXCL8. Another key finding is that NT, as well as the proinflammatory cytokines IL-1beta and TNF increase IL-37 gene expression in cultured human microglia. The data presented here highlight the connection between inflammation and ASD, supporting the development of IL-37 as a potential therapeutic agent of ASD.
